Abstract

Background: Vagus nerve stimulation (VNS) is a recent intervention for treatment-resistant depression. Electrophysiological recordings in the rat brain showed that VNS increases the firing rate of norepinephrine (NE) neurons after 1 day of stimulation and that of serotonin (5-HT) neurons after 14 days. This study was conducted to further characterize these effects.

Methods: We implanted rats with a VNS electrode and stimulator. We used the selective noradrenergic toxin DSP-4 to lesion NE neurons of the locus coeruleus. We recorded dorsal raphe 5-HT neurons under chloral hydrate anesthesia. We recorded hippocampus CA3 pyramidal neurons using 5-barreled iontophoretic pipettes.

Results: Analysis of a previously published data set revealed that VNS increased not only the spontaneous firing rates of NE neurons, but also the percentage of neurons firing in bursts. The enhancement of the 5-HT neuron firing rate by VNS was abolished by lesioning NE neurons. We found that VNS increased the degree of activation of postsynaptic α1-adrenoceptors on 5-HT neurons, probably through an increased release of endogenous NE. The tonic activation of postsynaptic 5-HT1A receptors in the hippocampus was enhanced after 14 days of VNS, as with other antidepressant treatments.

Limitations: Our study limitations include the fact that we turned off the stimulator during the electrophysiological recordings, which likely decreased the vagal tone to the brain. Also, we obtained the data while the animals were under anesthesia, therefore studies need to be carried out in unanesthetized rats to ascertain whether the anesthetic agent influenced the changes observed between control rats and those treated with VNS.

Conclusions: Vagus nerve stimulation initially increases the firing activity and pattern of NE neurons and subsequently those of 5-HT neurons, presumably as a cascade effect via α1-postsynaptic adrenoceptors. To date, VNS appears to be a unique antidepressant treatment increasing 5-HT transmission and enhancing the firing activity of NE neurons. These effects could contribute to the effectiveness of VNS in treatment-resistant depression.

Acknowledgements: We gratefully acknowledge the collaboration of the Quebec Coroner’s Office, as well as the cooperation and support of the next-of-kin of the deceased. We also thank Simon Spanswick for his technical advice and Dr. Joseph Rochford for his statistical expertise. The Quebec Brain Bank is supported in part by the Fonds de la recherche en santé du Québec (FRSQ). This research was supported by a Canadian Institutes of Health Research grant to Dr. Turecki and by a Douglas Institute start-up grant to Dr. Mechawar. Dr. Mechawar is also an FRSQ scholar.

Competing interests: None declared.

Contributors: Ms. Hercher, Dr. Parent, Ms. Canetti, Dr. Turecki and Dr. Mechawar designed the study. Ms. Hercher carried out the experiments, acquired the data and performed the statistical analyses. Ms. Hercher and Dr. Mechawar wrote the manuscript. Drs. Parent, Flores and Turecki also analyzed and interpreted the data. All authors reviewed the article and approved its publication.